Various publications are referenced herein either by author, and others by patent application numbers/patent numbers. The disclosures of these publications, patents and patent applications are hereby incorporated by reference in their entireties.
Injuries are a major cause of death throughout the world. Traffic accidents cause more than a million deaths annually, are the ninth leading cause of death globally and are expected to become the third leading cause of death and disability by 2020. Moreover, about 1.6 million people die as a result of intentional acts of interpersonal, collective or self-directed violence every year. More than 90% of trauma deaths occur in relatively poor countries. An additional factor contributing to hospital deaths is hemorrhage, considered to be responsible for about a third of in-hospital trauma deaths and constituting a contributory factor to death from multi-organ failure.
The haemostatic system helps to maintain the circulation after severe vascular injury, whether traumatic or surgical in origin. Major surgery and trauma trigger similar haemostatic responses and in both situations severe blood loss presents an extreme challenge to the coagulation system. Part of the undesired responses to surgery and trauma is stimulation of clot breakdown (fibrinolysis), which may, in some cases, become deleterious (hyper-fibrinolysis).
Antifibrinolytic agents reduce blood loss in patients with both normal and exaggerated fibrinolytic responses to surgery, without apparently increasing the risk of postoperative complications.
Tranexamic acid is a synthetic derivative of the amino acid lysine that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. A systematic review of randomised trials of tranexamic acid in patients undergoing elective surgery identified 53 studies including 3836 participants. Tranexamic acid reduced the need for blood transfusion by a third (Ker K. et al., BMC Emerg Med., 2012, 12:3).
Early administration of a short course of tranexamic acid reduced death, vascular occlusive events and the frequency of blood transfusions in trauma patients with significant hemorrhage or at risk for such an event (Ker K. ibid.).
The fibrinolytic cascade in mammals is composed by two principal components, the pro-enzyme plasminogen and two plasminogen activators tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA). Endogenous fibrinolysis begins by the binding of plasminogen to fibrin, the principal component of blood clots, flowed by its activation by tPA or uPA to the proteolytic active enzyme plasmin. The newly-generated plasmin cleaves fibrin clots into soluble fibrin degradation products (SFDP) that are usually taken up by the liver.
tPA is a trypsin-like serine protease that consists of five domains: a fibronectin finger-like domain (F), an epidermal growth factor domain (EGF), two kringle domains (K1 and K2), and a protease domain (P). In addition to the binding to its substrate plasminogen, tPA binds also to fibrin. Binding of tPA to fibrin is predominantly mediated by its finger domain and with some participation of K1 that also mediates its rapid clearance from the circulation (Stewart R et al., J Biol Chem. (2000), 275:10112-10120.)
uPA is expressed as a single-chain molecule (scuPA) composed of an N-terminal fragment (ATF; amino acids 1-135) and a protease domain (amino acids 136-411), also known as low molecular weight uPA (LMW-uPA). The amino-terminal fragment (ATF) is itself composed of 2 independent domains, the amino-terminal growth factor-like domain (GFD; amino acids 1-43), which is known to bind to the uPA receptor, and a single kringle (K; amino acids 47-135) (Rabbani S A et al., J Biol Chem. (1992), 267(20):14151-6; Bdeir K. et al., Blood. (2003), 102(10):3600-8). scuPA expresses plasminogen activator activity when converted to a 2-chain molecule (tcuPA) by plasmin (Stump D C et al., J Biol Chem. (1986), 261(36):17120-6) or as a single-chain molecule when bound to its receptor (Higazi A et al., J Biol Chem. (1995), 270(29):17375-80). Although in the process of plasminogen activation, tPA and uPA cleave the same single peptide bond between the amino acids Arg560 and Val561 in plasminogen, the mechanism of there fibrinolytic activities is totally different.
Fibrinolysis by tPA begins by the co-binding of tPA and plasminogen to fibrin, leading to a very high local concentrations of both agents on the clot surface and subsequent increase of the activation efficiency plasminogen by tPA by several orders of magnitude over that occurring in the absence of fibrin (Hoylaerts M et al., J Biol Chem. (1982), 257:2912-2919).
Although the presence of fibrin increases also the activation of plasminogen by uPA, uPA and in contrast to tPA, does not bind to fibrin (Collen D. et al, J Biol Chem. (1986), 261:1259-1266.). It has been shown that the binding of plasminogen to fibrin induces conformational changes in plasminogen that increases its affinity to uPA (Lijnen H R et al., J Biol Chem. (1986), 261(3):1253-8; Collen D. et al., Crit Rev Oncol Hematol. (1986), 4(3):249-301; Collen D. et al., J Biol Chem. (1978), 253:5395-5401).
Inhibitors of plasminogen activators can be used in any post-trauma situation, whether it affects the head, chest abdomen or other parts of the body. They could also be used in post partum bleeding, or during any surgery that may induce bleeding. An additional use could be in hemorrhagic stroke, subarachnoid hemorrhage or other conditions with an increased bleeding tendency, such as hemophilia or disseminated intravascular coagulation (DIC) patients and as biological glue.